KINETICS OF DRUG INTERACTIONS
Presented by
S.L.S(M. Pharm)
15AB1SO308
Under the esteemed guidance of
Prof.Dr.G.KISHORE BAB...
• Definition.
• Types of interactions.
• Factors contributing to drug interactions.
• Conclusion.
• Reference.
CONTENTS
10...
Drug interaction can be defined as the modifications of the effects of one drug by the
prior or concomitant administration...
Drugs likely involved in interactions
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 Drugs highly bound to plasma
proteins
 Used ...
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DI
Drug -Food
Drug-Herbal
Drug-DrugDrug-Disease
Drug-Alcohol
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Drug -Food
Interactions
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Drugs effect food By
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Food intake
Alteration
in gut flora
Nutrient
absorption
Nutrient...
How food can effect drugs
Increase
absorption
Decrease
absorption
Irritation
of
digestive
tract
No effect
• Rifampicin- wi...
Milk Fruit juice
Tea/coffee Alcohol
Swallowing of
the medicine
• Erythromycin
• Ketoconazole
• celiprolol
 Tetrcayclines
...
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DRUG – ALCOHOL
INTERACTIONS
In the absence of alcohol
After moderate alcohol
consumption
In chronic heavy drinkers
who are sober
In chronic heavy drin...
Class Names Interaction Effect
1. Analgesics Aspirin
Acetaminophen
 Increase gastric
emptying
 Toxic metabolite of
aceta...
Drug Drug Interactions
DI
Outside the
body
Syringe Iv fluids
Inside the
body
Pharmacoki
netic
Pharmacody
namic
10-12-2015 ...
Also called as incompatibility. It is a physicochemical interaction that occurs
when drugs are mixed in i.v . Infusions ca...
Interactions outside the body
• Mixing of the drugs in the same syringe
1. Thiopentone and succinylcholine.
2. Carbenicill...
• Giving drug in i.v infusion
1. Quinopristin and Dalfopristin.
2. Ampicillin, sodium salts of phenytoin, heparin.
10-12-2...
Unstable
Infuse within 2-
4hrs
Stable for
6-8 hrs
Stable for
12 hrs
Photosensitive
drugs
Not infused
after 6 hrs
Ampicilli...
Prevention of Pharmaceutical Interactions
1. Give iv drugs by bolus.
2. Do not add infusion solutions.
3. Avoid mixing of ...
“These interactions are those in which ADME properties of the object drug is
altered by the precipitant and hence such int...
Interactions inside the body
Absorbtion Distribution
Excretion Metabolism
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.
Drug interactions can effect the rate and the extent of systemic
drug absorption (Bioavailability)from the absorption si...
Surface
area
Motility
Alter GI
PH
Chelation &
Complexation
Alter
Intestinal
flora
Alter drug
transporter
s
10-12-2015 23Vi...
Drug-induced mucosal damage.
Antineoplastic agents: e.g., cyclophosphamide
vincristine
procarbazine
Inhibit absorption
of ...
Al 3+ , Mg 2+ + Prednisolone  Insoluble Complexes
Ca2+ + TC  Formation of chelating compounds
10-12-2015 Vignan pharmacy...
 Antacid (aluminum or magnesium hydroxide) Decrease absorption of
ciprofloxacin by 85%
due to chelation
 Cholestyramine ...
 The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT than the
ionized form does.
Alte...
antiacids Decrease the tablet
dissolution
of Ketoconazole (acidic)
H2 antagonists
Therefore, these drugs must be separated...
Forming an absorbtive layer
 Cholestyramine inhibits absorbtion of Digoxin,warfarin
 Sucralfate interferes with absorbti...
Altered Gut flora
 Bacterial flora has a marked role in metabolization
of some drugs.
 Long term antibiotics may kill no...
Metoclopramide
(antiemitic)
Increase absorption of cyclosporine due
to the increase of stomach empting time
Increase the t...
 Atropine/opiods  reduce absorption of drugs
 Purgatives  decrease absorbtion of digoxin
 Psyllium + Fibre + fluid 
...
Alteration of drug transporters
Oral drug inhibitor transporter
Digoxin quinidine P gp
Paclitaxel Cyclosporin P gp
Effect ...
TCA
Antipsychotics
Corticosteroids
Sulfonylureas
Methylphenidate
Fenfluramine
Dexfenfluramine
Sibutramine
Orlistat
appetit...
Beneficial absorbtion interactions
Metoclopramide
Increases gastric emptying
Increases absorbtion of
analgesic in treatmen...
There is an important factor :
Vd
Protein binding interactions :
- unbound molecules remain free and pharmacological activ...
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Displacement from
tissue binding site
Displacement from
protein binding site
Impaired...
2. Displacement from plasma protein binding
Can be clinically important if 2 criteria are fulfilled
 Drug should be highl...
 Warfarin (99% bound) and Phenytoin (90% bound)
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Fig:14 Fig:15
Metabolism (biotransformation) Interactions
• Most drugs are chemically altered within Liver to less
toxic and less lipid-...
Pathways of drug metabolism
CYP450
Pathways of drug metabolism
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• CYP450 most important isoenzymes responsible
for liver metabolism.
– CYP 3A4
– CYP 2D6
– CYP 2C8
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Metabolism
Enzyme Induction
S No. Precipitant drug Object drug
1. Alcohol Warfarin, Phenytoin
2. Barbiturates Chlorpromazi...
Metabolism
Enzyme Inhibition
S No. Precipitant Drug Enzyme Object drug
1. Allopurinol Xanthine Oxidase Azathioprine
2. Car...
S.no Precipitant drug Object drug Effect
1. Cimetidine Diazepam CNS effects
2. Macrolides Theophylline Cardiac toxicity
3....
Alteration in nutrient metabolism
Ex:
 Anticoagulant drug warfarin and vitamin K
 Statins inhibit HMG –CoA Reductase inh...
Excretion Interactions
• Most drug are excreted in Urine or Bile.
• Some drugs are reabsorbed from renal tubules or
entero...
Mechanisms :
• Altered urine PH
 Change in active tubular secretion.
Some drugs may compete for excretion.
E.g. probenec...
Excretion
S. No. Precipitant Drug Object Drug Result
1. Probenecid Penicillin Penicillin Retention
2. Quinidine Digoxin Di...
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Fig:19
Alteration in nutrient excretion
• D- penicillamine & EDTA binds metals Zn2+ and eliminates it via urine.
• Diuretics cau...
Pharmacodynamic Interactions
A) Direct Pharmacodynamic Interactions
1. Antagonism at same site
● Opiates with Naloxone
● W...
2. Synergism at same site
● Effects of depolarising skeletal muscle relaxants potentiated
by antibiotics like aminoglycosi...
Dihydropteroate diphosphate+ P-aminobenzoic acid(PABA)
Dihydropteroate synthetase sulfonamides
Dihydropteroic acid
Dihydro...
3. Summation of similar effects at different sites
● Effect of alcohol as a depressant potentiated by other
centrally acti...
B) Indirect Pharmacodynamic Interactions
1. Cardiovascular system
 Loss of Antihypertensive action of ACEI with NSAIDS
 ...
DRUG HERB
INTERACTION
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HERBS
Betel Nuts
Area Catechu
• Contains
arecoline
• Extrapyramida
l symptoms
Ginkgo Biloba
• Inhibits PAF
• spontaneous
S...
• Polypharmacy people (elder)
• Hepatic disorders
• Renal disorders
• Genetic factors
Patients in high risk of drug intera...
PHARMACIST’S ROLE IN DRUG INTERACTIONS
Advising
Monitoring
Reporting
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Fig:26
Fig:27
 Health care professionals and pharmacists have to play an important role in giving
advisory knowledge on monitoring conc...
REFERENCES
 LEON SHARGEL, ALANH.MUTNICK, PAULF.SOUNEY, LARRY
N.SWANSON, Comprehensive Pharmacy Review, Eight edition,
Pg....
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Online Drug Interaction
Checker
http://reference.medscape.com/drug-interactioncheck...
THANKS
TO
ALL
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of 64

kinetics of drug interactions

related to drug interactions
Published on: Mar 3, 2016
Published in: Health & Medicine      
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Transcripts - kinetics of drug interactions

  • 1. KINETICS OF DRUG INTERACTIONS Presented by S.L.S(M. Pharm) 15AB1SO308 Under the esteemed guidance of Prof.Dr.G.KISHORE BABU., M.Pharm ., Ph.D. HOD, Department Of Pharmaceutics VIGNAN PHARMACY COLLEGE (Approved by AICTE, PCI & Affiliated to JNTU KAKINADA) VADLAMUDI, GUNTUR DIST, ANDHRA PRADESH, INDIA,PIN:522 213 2015 10-12-2015 1Vignan pharmacy college
  • 2. • Definition. • Types of interactions. • Factors contributing to drug interactions. • Conclusion. • Reference. CONTENTS 10-12-2015 2Vignan pharmacy college
  • 3. Drug interaction can be defined as the modifications of the effects of one drug by the prior or concomitant administration of another drug. Drug that precipitates the interaction - Precipitant drug Drug whose action is affected - Object drug DEFINITION 10-12-2015 3Vignan pharmacy college
  • 4. Drugs likely involved in interactions 10-12-2015 Vignan pharmacy college 4  Drugs highly bound to plasma proteins  Used for long term  Enzyme inducers or inhibitors  Two drugs simultaneously given for same disease Precipitating drugs • Narrow therapeutic index • Zero order kinetics Object Drugs
  • 5. 10-12-2015 Vignan pharmacy college 5
  • 6. DI Drug -Food Drug-Herbal Drug-DrugDrug-Disease Drug-Alcohol 10-12-2015 6Vignan pharmacy college
  • 7. Drug -Food Interactions 10-12-2015 Vignan pharmacy college 7
  • 8. Drugs effect food By 10-12-2015 Vignan pharmacy college 8 Food intake Alteration in gut flora Nutrient absorption Nutrient metabolism Nutrient excretion
  • 9. How food can effect drugs Increase absorption Decrease absorption Irritation of digestive tract No effect • Rifampicin- without food • Rifabutin- with food • Rifapentin- no effect of food 10-12-2015 Vignan pharmacy college 9
  • 10. Milk Fruit juice Tea/coffee Alcohol Swallowing of the medicine • Erythromycin • Ketoconazole • celiprolol  Tetrcayclines  Bisacodyl  Iron supplements  Mercaptopurin • Wine-tyramine reaction • iron absorbtion • theophylline 10-12-2015 Vignan pharmacy college 10
  • 11. 10-12-2015 Vignan pharmacy college 11 DRUG – ALCOHOL INTERACTIONS
  • 12. In the absence of alcohol After moderate alcohol consumption In chronic heavy drinkers who are sober In chronic heavy drinkers who are intoxicated 10-12-2015 12Vignan pharmacy college
  • 13. Class Names Interaction Effect 1. Analgesics Aspirin Acetaminophen  Increase gastric emptying  Toxic metabolite of acetaminophen Faster alcohol absorbtion Liver damage 2. Anticonvulsant Phenytoin Induces phenytoin breakdown Decrease effect 3. Antihistamines Chlorpheniramine Increase CNS effect sedation 4. Antidiabetics Chlorpropamide Glyburide Metformin Increase risk of hypoglycemia Unconsciousness Disulfiram like reaction Lactic acidosis 5. BZDs Diazepam Increase effect Sedation 10-12-2015 13Vignan pharmacy college Table:1
  • 14. Drug Drug Interactions DI Outside the body Syringe Iv fluids Inside the body Pharmacoki netic Pharmacody namic 10-12-2015 Vignan pharmacy college 14
  • 15. Also called as incompatibility. It is a physicochemical interaction that occurs when drugs are mixed in i.v . Infusions causing precipitation or inactivation of active principles . Example:- Ampicillin , chlorpromazine & barbituates interact with dextran in solutions and are broken down or form chemical compounds. Pharmaceutical interactions 10-12-2015 15Vignan pharmacy college
  • 16. Interactions outside the body • Mixing of the drugs in the same syringe 1. Thiopentone and succinylcholine. 2. Carbenicillin inactivate aminoglycosides. 3. Hydrocortisone inactivates penicillins. 10-12-2015 16Vignan pharmacy college Fig:1
  • 17. • Giving drug in i.v infusion 1. Quinopristin and Dalfopristin. 2. Ampicillin, sodium salts of phenytoin, heparin. 10-12-2015 Vignan pharmacy college 17 Fig:2
  • 18. Unstable Infuse within 2- 4hrs Stable for 6-8 hrs Stable for 12 hrs Photosensitive drugs Not infused after 6 hrs Ampicillin Benzyl penicillin Fluoxacillin Amphoterecin Cephaloridine Erythromycin Diazepam Tetracycline Dacarbazine colistin Stability of drugs in Saline or Dextrose solution 10-12-2015 Vignan pharmacy college 18 Table:2
  • 19. Prevention of Pharmaceutical Interactions 1. Give iv drugs by bolus. 2. Do not add infusion solutions. 3. Avoid mixing of drugs in the same infusion. 4. Mix the drug thoroughly in the infusion. 5. Use 2 separate infusion sites if drugs administered simultaneously . 10-12-2015 19Vignan pharmacy college Fig:3
  • 20. “These interactions are those in which ADME properties of the object drug is altered by the precipitant and hence such interactions are also called as ADME interactions”. •The resultant effect is altered plasma concentration of the object drug. PHARMACOKINETIC INTERACTIONS 10-12-2015 20Vignan pharmacy college
  • 21. Interactions inside the body Absorbtion Distribution Excretion Metabolism 10-12-2015 21Vignan pharmacy college
  • 22. . Drug interactions can effect the rate and the extent of systemic drug absorption (Bioavailability)from the absorption site, resulting in increased or decreased drug bioavailability. • Faster or slower drug absorption. • More, or, less complete drug absorption. Absorption interactions 10-12-2015 22Vignan pharmacy college Fig:4
  • 23. Surface area Motility Alter GI PH Chelation & Complexation Alter Intestinal flora Alter drug transporter s 10-12-2015 23Vignan pharmacy college Fig:5
  • 24. Drug-induced mucosal damage. Antineoplastic agents: e.g., cyclophosphamide vincristine procarbazine Inhibit absorption of several drugs eg., digoxin Surface area 10-12-2015 Vignan pharmacy college 24
  • 25. Al 3+ , Mg 2+ + Prednisolone  Insoluble Complexes Ca2+ + TC  Formation of chelating compounds 10-12-2015 Vignan pharmacy college 25 Chelation and Complexation Fig:6 Fig:7 Fig:8
  • 26.  Antacid (aluminum or magnesium hydroxide) Decrease absorption of ciprofloxacin by 85% due to chelation  Cholestyramine + Digoxin and Warfarin (Resin) BA of Digoxin and Warfarin  Sodium polystyrene + cations Renal clearence of bicorbonate resulting in systemic acidosis 10-12-2015 Vignan pharmacy college 26
  • 27.  The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. Alteration in pH PH Absorption of weak acids PH Absorption of weak bases 10-12-2015 27Vignan pharmacy college Fig:9
  • 28. antiacids Decrease the tablet dissolution of Ketoconazole (acidic) H2 antagonists Therefore, these drugs must be separated by at least 2h in the time of administration of both . Increases absorption of weak bases like Anti coagulents, warfarin, phenyl butazone 10-12-2015 28Vignan pharmacy college
  • 29. Forming an absorbtive layer  Cholestyramine inhibits absorbtion of Digoxin,warfarin  Sucralfate interferes with absorbtion of Phenytoin 10-12-2015 29Vignan pharmacy college Fig:10
  • 30. Altered Gut flora  Bacterial flora has a marked role in metabolization of some drugs.  Long term antibiotics may kill normal flora and affect drug absorption. Ex : erythromycin and digoxin 40% or more of the administered digoxin dose is metabolised by the intestinal flora. Coadministration of antibiotics leads to increase in digoxin levels. 10-12-2015 30Vignan pharmacy college Fig:11
  • 31. Metoclopramide (antiemitic) Increase absorption of cyclosporine due to the increase of stomach empting time Increase the toxicity of cyclosporine Altered gastric emptying 10-12-2015 31Vignan pharmacy college Fig:12
  • 32.  Atropine/opiods  reduce absorption of drugs  Purgatives  decrease absorbtion of digoxin  Psyllium + Fibre + fluid  Increase in gi motility & decrease the time available for coadministered drugs to be absorbed 10-12-2015 32Vignan pharmacy college
  • 33. Alteration of drug transporters Oral drug inhibitor transporter Digoxin quinidine P gp Paclitaxel Cyclosporin P gp Effect on Transporters 10-12-2015 33Vignan pharmacy college Table:3 Fig:13
  • 34. TCA Antipsychotics Corticosteroids Sulfonylureas Methylphenidate Fenfluramine Dexfenfluramine Sibutramine Orlistat appetite appetite Alteration in appetite 10-12-2015 Vignan pharmacy college 34
  • 35. Beneficial absorbtion interactions Metoclopramide Increases gastric emptying Increases absorbtion of analgesic in treatment of acute attack of migraine 10-12-2015 35Vignan pharmacy college
  • 36. There is an important factor : Vd Protein binding interactions : - unbound molecules remain free and pharmacological active. - bound molecules are pharmacological inactive. Some drugs may compete others for binding to protein depending on affinity and concentration. Distribution Interactions 10-12-2015 36Vignan pharmacy college
  • 37. 10-12-2015 37Vignan pharmacy college Displacement from tissue binding site Displacement from protein binding site Impaired renal excretion Quinidine given to a patient on digoxin 1. Displacement from tissue binding sites
  • 38. 2. Displacement from plasma protein binding Can be clinically important if 2 criteria are fulfilled  Drug should be highly protein bound (>90%)  Low apparent volume of distribution Precipitant drugs involved 1. Salicylates 2. Phenylbutazone 3. Sulfonamides 10-12-2015 38Vignan pharmacy college
  • 39.  Warfarin (99% bound) and Phenytoin (90% bound) 10-12-2015 39Vignan pharmacy college Fig:14 Fig:15
  • 40. Metabolism (biotransformation) Interactions • Most drugs are chemically altered within Liver to less toxic and less lipid-soluble metabolites. • Hepatic metabolism has two pathways : – Phase 1 (modification) – Phase 11 (conjugation) 10-12-2015 40Vignan pharmacy college Fig:16
  • 41. Pathways of drug metabolism CYP450 Pathways of drug metabolism 10-12-2015 41Vignan pharmacy college
  • 42. • CYP450 most important isoenzymes responsible for liver metabolism. – CYP 3A4 – CYP 2D6 – CYP 2C8 10-12-2015 42Vignan pharmacy college Fig:17
  • 43. Metabolism Enzyme Induction S No. Precipitant drug Object drug 1. Alcohol Warfarin, Phenytoin 2. Barbiturates Chlorpromazine, Phenytoin 3. Phenytoin Tolbutamide 4. Rifampicin Warfarin, Tolbutamide 5. St. John’s Wort Carbamazepine, SSRIs, Warfarin 10-12-2015 43Vignan pharmacy college Table:4
  • 44. Metabolism Enzyme Inhibition S No. Precipitant Drug Enzyme Object drug 1. Allopurinol Xanthine Oxidase Azathioprine 2. Carbidopa Dopa decarboxylase L-Dopa 3. Disulfiram Aldehyde dehydrogenase Alcohol 4. MAO Inhibitors Monomine Oxidase Amine containing foods 10-12-2015 44Vignan pharmacy college Table:5
  • 45. S.no Precipitant drug Object drug Effect 1. Cimetidine Diazepam CNS effects 2. Macrolides Theophylline Cardiac toxicity 3. Metronidazole Alcohol Disulfiram like action 4. Chloramphenicol Tolbutamide Hypoglycemia Enzyme Inhibition 10-12-2015 45Vignan pharmacy college Table:6
  • 46. Alteration in nutrient metabolism Ex:  Anticoagulant drug warfarin and vitamin K  Statins inhibit HMG –CoA Reductase inhibitor – precursor for cholesterol and coenzyme Q10 10-12-2015 46Vignan pharmacy college
  • 47. Excretion Interactions • Most drug are excreted in Urine or Bile. • Some drugs are reabsorbed from renal tubules or enterohepatic recirculation. • Some drugs are excreted in acidic urine, so changing urine PH will affect there serum level. • These interaction is rare. 10-12-2015 47Vignan pharmacy college Fig:18
  • 48. Mechanisms : • Altered urine PH  Change in active tubular secretion. Some drugs may compete for excretion. E.g. probenecid and penicillin.  Enterohepatic recirculation. E.g. penicillins and oral contraceptives. 10-12-2015 48Vignan pharmacy college
  • 49. Excretion S. No. Precipitant Drug Object Drug Result 1. Probenecid Penicillin Penicillin Retention 2. Quinidine Digoxin Digoxin Toxicity 3. Salicylates Methotrextate Methotrexate toxicity 4. Salicylates Uricosuric Drugs Reduced Uricosuria 10-12-2015 49Vignan pharmacy college Table:7
  • 50. 10-12-2015 50Vignan pharmacy college Fig:19
  • 51. Alteration in nutrient excretion • D- penicillamine & EDTA binds metals Zn2+ and eliminates it via urine. • Diuretics cause loss of ions such as Mg 2+ ,K+ ,Na+ , Ca 2+. 10-12-2015 Vignan pharmacy college 51
  • 52. Pharmacodynamic Interactions A) Direct Pharmacodynamic Interactions 1. Antagonism at same site ● Opiates with Naloxone ● Warfarin with Vitamin K  These interactions occur when the pharmacodynamic effect of the drug is alter by another drug, chemical ,or food element, producing an antagonistic, synergistic , or addtive effect 10-12-2015 52Vignan pharmacy college Fig:20
  • 53. 2. Synergism at same site ● Effects of depolarising skeletal muscle relaxants potentiated by antibiotics like aminoglycosides, polymixin B 10-12-2015 53Vignan pharmacy college
  • 54. Dihydropteroate diphosphate+ P-aminobenzoic acid(PABA) Dihydropteroate synthetase sulfonamides Dihydropteroic acid Dihydrofolic acid × trimethoprim Tetrahydro folic acid × 10-12-2015 54Vignan pharmacy college Fig:21
  • 55. 3. Summation of similar effects at different sites ● Effect of alcohol as a depressant potentiated by other centrally acting drugs ● Effect of trimethoprim and sulfamethoxazole 10-12-2015 Vignan pharmacy college 55
  • 56. B) Indirect Pharmacodynamic Interactions 1. Cardiovascular system  Loss of Antihypertensive action of ACEI with NSAIDS  Bradycardia- beta blockers + verapamil 10-12-2015 56Vignan pharmacy college 2. Fluid and electrolyte imbalance  Thiazide and loop diuretics - hypokalemia 3. CNS  Sedation- BZD+ Alcohol
  • 57. DRUG HERB INTERACTION 10-12-2015 57Vignan pharmacy college
  • 58. HERBS Betel Nuts Area Catechu • Contains arecoline • Extrapyramida l symptoms Ginkgo Biloba • Inhibits PAF • spontaneous Subarachnoid hemorrhage St. Johns Wort Hypericum perforatin • Inducer of CYP3A4 • May elevate serotonin Garlic Allium sativum • Increases INR • Post operative bleeding Liquorice Glycyrrhizin • Inhibits degradation of cortisol 10-12-2015 58Vignan pharmacy college
  • 59. • Polypharmacy people (elder) • Hepatic disorders • Renal disorders • Genetic factors Patients in high risk of drug interactions 10-12-2015 59Vignan pharmacy college Fig:22 Fig:23 Fig:24 Fig:25
  • 60. PHARMACIST’S ROLE IN DRUG INTERACTIONS Advising Monitoring Reporting 10-12-2015 60Vignan pharmacy college Fig:26 Fig:27
  • 61.  Health care professionals and pharmacists have to play an important role in giving advisory knowledge on monitoring concurrent use of herbal and conventional medicines and to collect data for suspected drug interactions. We need to bring into lime light about the drug interactions 10-12-2015 61Vignan pharmacy college
  • 62. REFERENCES  LEON SHARGEL, ALANH.MUTNICK, PAULF.SOUNEY, LARRY N.SWANSON, Comprehensive Pharmacy Review, Eight edition, Pg.no: 271-276 10-12-2015 62Vignan pharmacy college  ROGER WALKER & CATE WHITTLESEA, Clinical Pharmacy and Therapeutics, 5th Edition, Pg.no: 52-59
  • 63. 10-12-2015 Vignan pharmacy college 63 Online Drug Interaction Checker http://reference.medscape.com/drug-interactionchecker ,,,,,,, https://online.epocrates.com/u/1300/MultiCheck?ICID =search-DDI ,,,,,, http://www.drugs.com/drug_interactions.html
  • 64. THANKS TO ALL 10-12-2015 64Vignan pharmacy college

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